Abstract IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. Due to lack of disease-specific therapy, many patients progress to end-stage renal disease. IgAN is defined by the characteristic IgA1 mesangial deposits. Based on our published data, we have developed an original pathogenesis model that describes sequential steps and molecular candidates for the development of disease. This model is recognized by other researchers in the field as a blueprint for development of disease-specific biomarkers and treatments. In the past funding period, we demonstrated that the majority of IgAN patients, regardless of age and ethnicity, have immunologic defects resulting in generation of pathogenic IgA1- containing immune complexes. We have further shown that the pathogenic immune complexes consist of IgA1 with some O-glycans deficient in galactose (Gd-IgA1), although Gd-IgA1 alone is not sufficient to induce IgAN. A second critical step in the pathogenesis of IgAN is the development of autoantibodies that bind Gd-IgA1 and form pathogenic immune complexes. Our new data revealed that IgG extracted from glomerular deposits of IgAN patients is specific for Gd-IgA1. Importantly, serum levels of Gd-IgA1 (autoantigen) and IgG autoantibodies specific for Gd-IgA1 each correlate with disease severity and progression. Our analyses also revealed the presence of complement proteins in Gd-IgA1-IgG circulating immune complexes. This finding is consistent with our GWAS that identified a major role for a common deletion of the complement factor H- related factors 1 and 3 (CFHR 1,3 del) that impacts C3 activation. We have identified major activation pathways induced by Gd-IgA1-IgG complexes in primary human mesangial cells and shown that blockade of the initial signaling steps prevented aberrant cellular activation. Moreover, we have begun to validate these findings in a novel mouse model of IgAN we developed. In this revised competing renewal application, we hypothesize that, in individuals with an autoimmune predisposition, elevated Gd-IgA1 is associated with the development of IgG autoantibodies specific for Gd-IgA1. These events direct the formation of pathogenic immune complexes and additional proteins modulate the pathogenic potential of these complexes, thus affecting disease presentation and progression. We will follow-up our findings using unique, clinically and genetically well-characterized, cohorts of IgAN patients. We will define the biological and clinical impact of IgG autoantibodies, including the timeline for production before disease onset (Aim 1). We will assess the composition of Gd-IgA1-IgG immune complexes in the circulation vs. in the glomerular deposits (IgG subclasses, complement proteins) (Aim 2) and determine the role of complement in biological activity of the pathogenic Gd-IgA1-IgG complexes (Aim 3). Relevance: Our studies will define factors associated with development and progression of IgAN and thus provide information concerning stratification of patients for clinical trials and development of a future disease-specific therapy.